The growth factor-like lysophospholipids lysophosphatidic acid (LPA) and sphingosine-1-phosphate (S1P) regulate many fundamental cellular responses, including cell survival, cell proliferation, cellular motility and migration. LPA has been shown to have profound activity in preventing apoptosis and rescuing cells from the progression of the apoptotic cascade. An LPA mimic, octadecenyl thiophosphate (OTP) (Durgam et al., Synthesis and pharmacological evaluation of second-generation phosphatidic acid derivatives as lysophosphatidic acid receptor ligands. Bioorg Med Chem Lett (2006) 16(3): 633-640), has demonstrated superior efficacy in vitro and in vivo, as compared to LPA, in rescuing cells and animals from radiation-induced apoptosis (Deng et al., The lysophosphatidic acid type 2 receptor is required for protection against radiation-induced intestinal injury. Gastroenterology (2007) 132(5): 1834-1851).
The G protein-coupled lysophosphatidic acid 2 (LPA2) receptor elicits prosurvival responses to prevent and rescue cells from apoptosis. LPA2 stimulation provides protection from chemotherapeutic agent-induced apoptosis and radiation-induced apoptosis. Highly effective LPA2-specific agonists may therefore have significant therapeutic value.
Development of LPA-based drug candidates has thus far been limited to the discovery of lipid-like ligands, primarily to address the hydrophobic environment of the S1P and LPA G protein-coupled receptor (GPCR) ligand binding pockets. Only a few LPA receptor ligands utilize nonlipid structural features, including Ki16425, an LPA1/2/3 antagonist (Ohta et al., Ki16425, a subtype-selective antagonist for EDG-family lysophosphatidic acid receptors. Mol Pharmacol (2003) 64(4): 994-1005), and the AM095-152 series of LPA1-selective compounds (Swaney et al., Pharmacokinetic and pharmacodynamic characterization of an oral lysophosphatidic acid type 1 receptor-selective antagonist. J Pharmacol Exp Ther (2011) 336(3): 693-700). A major obstacle in developing LPA analogs is their high degree of hydrophobicity that makes these agents non-ideal drug candidates. Another complicating factor is the multiplicity of LPA GPCRs, which represents a significant challenge to the development of compounds specific to a single target such as LPA2.
There are pharmacological advantages to the use of non-lipid molecules as pharmaceutical agents. Discovery and development of drug-like non-lipid compounds might produce even more efficacious molecules that can interact with LPA receptors in ways that will produce desirable cellular and systemic effects.